Respiratory failure is the leading cause of morbidity and mortality in people with acute and chronic cervical spinal cord injury (SCI). Thus, therapeutic approaches that restore respiratory function can significantly improve a person[unreadable]s quality of life. Our proposal is highly significant because: 1) we propose investigating a therapeutic strategy that may be more efficacious beyond the immediate post-injury period, 2) our pharmacological agents are already available to treat other clinical diseases, and 3) our proposal will utilize inherent mechanisms of spinal plasticity without the need for exogenous materials such as cellular or tissue transplantation. Our laboratory investigates functional plasticity of phrenic motoneurons, which innervate the primary inspiratory muscle in mammals - the diaphragm. Phrenic motor output is positively correlated to tidal volume;therefore, increasing phrenic motoneuron activity can improve tidal volume after SCI. Our approach uses small, highly permeable molecules (adenosine A2a receptor agonists) that mimic the effects of brain- derived neurotrophic factor (BDNF) on phrenic motoneuron activity (i.e., elicits a persistent increase in phrenic motor output). In PC12 cells, the A2a receptor agonist CGS 21680 mimics neurotrophins by transactivating their tropomyosin-related kinase (Trk) receptors in the absence of Trk ligands. We recently demonstrated that cervical spinal administration of CGS 21680 strengthens spinal synaptic connections to phrenic motoneurons and elicits long-term increases in phrenic motor output below a cervical SCI. A2a-induced phrenic motor facilitation requires TrkB receptor phosphorylation but does not require the TrkB ligand, BDNF. Thus, we propose that A2a receptor agonists transactivate TrkB receptors in vivo. The magnitude of A2a-induced phrenic motor facilitation increases with time post-injury, suggesting that A2a-induced phrenic motor recovery is particularly efficacious in the chronically injured population. Demonstrating clear translational potential, intraperitoneal injections of CGS 21680 also elicits long-lasting improvements in tidal volume in awake rats with cervical SCI. Thus, we propose that A2a receptor agonists represent a novel pharmacological approach to improve breathing in spinally injured rats. We will test our hypothesis that A2a receptor agonists elicit long-lasting improvements in tidal volume by using whole-body plethysmography. Strengths of this proposal include: 1) assessment of breathing in awake freely behaving spinally injured animals, 2) use of a clinically relevant injury model, C4 lateralized contusions, and 3) the availability of the Veterinary Clinical Investigations Center, at the University of Pennsylvania, to develop our pharmacological approach into preclinical trials. The proposed experiments are highly significant because they may demonstrate a novel approach to improve respiratory motor function after chronic SCI. Such an approach may be extrapolated to other motor deficits (i.e., locomotion, bladder control, and sexual function) that occur secondary to impaired motoneuron function in a variety of neurological disorders (i.e., SCI and ALS). Spinal cord injury causes life-threatening respiratory failure by decreasing function of the neural cells that control respiratory muscles, the respiratory motoneurons. One approach to improve breathing is to identify and manipulate the mechanisms whereby respiratory motoneurons adapt to long-term changes in demand. To this end, we propose investigating a promising pharmacological approach that persistently increases respiratory motoneuron function, thereby improving breathing after spinal cord injury.